Our initial focus is on MCD, a syndrome in which infected B cells are in the lytic phase of the viral replication cycle. Infected cells express several KSHV structural glycoproteins at the surface, including gH/gL, gB, and K8.1A. Though a relatively rare disease, MCD incidence continues to rise despite antiretroviral therapy and the associated improvements in immune function. MCD if a life-threatening disease (median life expectancy <3 years after diagnosis), and no standards for clinical management have been developed. Hence immunotoxins to selectively kill infected B cells may prove beneficial. We previously reported the design and characterization of two new PE-based immunotoxins targeting gH, developed from murine mAbs isolated in our laboratory. One of these, YC15-PE38, was found to directly kill gH transfectant cell lines with high potency (IC50 150 pM). When tested against Vero-219 cells carrying an episomal recombinant KSHV genome, the immunotoxin potently inhibited virus production (IC50 500 pM);controls verified that this effect was due to selective killing of the virus-producing cells. In combination drug experiments, the immunotoxin and ganciclovir demonstrated complementary inhibitory activities against infectious virus production form Vero-219 cells. In a collaborative effort (B. Chandran), we have produced an immunotoxin against K8.1A that also displays activity against virus production from Vero-219 cells.